The hidden diversity of vascular patterns in flower heads.

Vascular systems are intimately related to the shape and spatial arrangement of the plant organs they support. We investigate the largely unexplored association between spiral phyllotaxis and the vascular system in Asteraceae flower heads. We imaged heads of eight species using synchrotron-based X-ray micro-computed tomography and applied original virtual reality and haptic software to explore head vasculature in three dimensions. We then constructed a computational model to infer a plausible patterning mechanism. The vascular system in the head of the model plant Gerbera hybrida is qualitatively different from those of Bellis perennis and Helianthus annuus, characterized previously. Cirsium vulgare, Craspedia globosa, Echinacea purpurea, Echinops bannaticus, and Tanacetum vulgare represent variants of the Bellis and Helianthus systems. In each species, the layout of the main strands is stereotypical, but details vary. The observed vascular patterns can be generated by a common computational model with different parameter values. In spite of the observed differences of vascular systems in heads, they may be produced by a conserved mechanism. The diversity and irregularities of vasculature stand in contrast with the relative uniformity and regularity of phyllotactic patterns, confirming that phyllotaxis in heads is not driven by the vasculature.

Correction: Ethical challenges of using remote monitoring technologies for clinical research: A case study of the role of local research ethics committees in the RADAR-AD study.

[This corrects the article DOI: 10.1371/journal.pone.0285807.].

Characterisation of Cognitive Load Using Machine Learning Classifiers of Electroencephalogram Data.

A high cognitive load can overload a person, potentially resulting in catastrophic accidents. It is therefore important to ensure the level of cognitive load associated with safety-critical tasks (such as driving a vehicle) remains manageable for drivers, enabling them to respond appropriately to changes in the driving environment. Although electroencephalography (EEG) has attracted significant interest in cognitive load research, few studies have used EEG to investigate cognitive load in the context of driving. This paper presents a feasibility study on the simulation of various levels of cognitive load through designing and implementing four driving tasks. We employ machine learning-based classification techniques using EEG recordings to differentiate driving conditions. An EEG dataset containing these four driving tasks from a group of 20 participants was collected to investigate whether EEG can be used as an indicator of changes in cognitive load. The collected dataset was used to train four Deep Neural Networks and four Support Vector Machine classification models. The results showed that the best model achieved a classification accuracy of 90.37%, utilising statistical features from multiple frequency bands in 24 EEG channels. Furthermore, the Gamma and Beta bands achieved higher classification accuracy than the Alpha and Theta bands during the analysis. The outcomes of this study have the potential to enhance the Human-Machine Interface of vehicles, contributing to improved safety.

Data sharing in neurodegenerative disease research: challenges and learnings from the innovative medicines initiative public-private partnership model.

Efficient data sharing is hampered by an array of organizational, ethical, behavioral, and technical challenges, slowing research progress and reducing the utility of data generated by clinical research studies on neurodegenerative diseases. There is a particular need to address differences between public and private sector environments for research and data sharing, which have varying standards, expectations, motivations, and interests. The Neuronet data sharing Working Group was set up to understand the existing barriers to data sharing in public-private partnership projects, and to provide guidance to overcome these barriers, by convening data sharing experts from diverse projects in the IMI neurodegeneration portfolio. In this policy and practice review, we outline the challenges and learnings of the WG, providing the neurodegeneration community with examples of good practices and recommendations on how to overcome obstacles to data sharing. These obstacles span organizational issues linked to the unique structure of cross-sectoral, collaborative research initiatives, to technical issues that affect the storage, structure and annotations of individual datasets. We also identify sociotechnical hurdles, such as academic recognition and reward systems that disincentivise data sharing, and legal challenges linked to heightened perceptions of data privacy risk, compounded by a lack of clear guidance on GDPR compliance mechanisms for public-private research. Focusing on real-world, neuroimaging and digital biomarker data, we highlight particular challenges and learnings for data sharing, such as data management planning, development of ethical codes of conduct, and harmonization of protocols and curation processes. Cross-cutting solutions and enablers include the principles of transparency, standardization and co-design - from open, accessible metadata catalogs that enhance findability of data, to measures that increase visibility and trust in data reuse.

Ethical challenges of using remote monitoring technologies for clinical research: A case study of the role of local research ethics committees in the RADAR-AD study.

INTRODUCTION: Clinical research with remote monitoring technologies (RMTs) has multiple advantages over standard paper-pencil tests, but also raises several ethical concerns. While several studies have addressed the issue of governance of big data in clinical research from the legal or ethical perspectives, the viewpoint of local research ethics committee (REC) members is underrepresented in the current literature. The aim of this study is therefore to find which specific ethical challenges are raised by RECs in the context of a large European study on remote monitoring in all syndromic stages of Alzheimer's disease, and what gaps remain. METHODS: Documents describing the REC review process at 10 sites in 9 European countries from the project Remote Assessment of Disease and Relapse-Alzheimer's Disease (RADAR-AD) were collected and translated. Main themes emerging in the documents were identified using a qualitative analysis approach. RESULTS: Four main themes emerged after analysis: data management, participant's wellbeing, methodological issues, and the issue of defining the regulatory category of RMTs. Review processes differed across sites: process duration varied from 71 to 423 days, some RECs did not raise any issues, whereas others raised up to 35 concerns, and the approval of a data protection officer was needed in half of the sites. DISCUSSION: The differences in the ethics review process of the same study protocol across different local settings suggest that a multi-site study would benefit from a harmonization in research ethics governance processes. More specifically, some best practices could be included in ethical reviews across institutional and national contexts, such as the opinion of an institutional data protection officer, patient advisory board reviews of the protocol and plans for how ethical reflection is embedded within the study.

Senescent cardiomyocytes contribute to cardiac dysfunction following myocardial infarction.

Myocardial infarction is a leading cause of morbidity and mortality. While reperfusion is now standard therapy, pathological remodeling leading to heart failure remains a clinical problem. Cellular senescence has been shown to contribute to disease pathophysiology and treatment with the senolytic navitoclax attenuates inflammation, reduces adverse myocardial remodeling and results in improved functional recovery. However, it remains unclear which senescent cell populations contribute to these processes. To identify whether senescent cardiomyocytes contribute to disease pathophysiology post-myocardial infarction, we established a transgenic model in which p16 (CDKN2A) expression was specifically knocked-out in the cardiomyocyte population. Following myocardial infarction, mice lacking cardiomyocyte p16 expression demonstrated no difference in cardiomyocyte hypertrophy but exhibited improved cardiac function and significantly reduced scar size in comparison to control animals. This data demonstrates that senescent cardiomyocytes participate in pathological myocardial remodeling. Importantly, inhibition of cardiomyocyte senescence led to reduced senescence-associated inflammation and decreased senescence-associated markers within other myocardial lineages, consistent with the hypothesis that cardiomyocytes promote pathological remodeling by spreading senescence to other cell-types. Collectively this study presents a novel demonstration that senescent cardiomyocytes are major contributors to myocardial remodeling and dysfunction following a myocardial infarction. Therefore, to maximize the potential for clinical translation, it is important to further understand the mechanisms underlying cardiomyocyte senescence and how to optimize senolytic strategies to target this cell lineage.

Broadened assessments, health education and cognitive aids in the remote memory clinic.

The prevalence of dementia is increasing and poses a health challenge for individuals and society. Despite the desire to know their risks and the importance of initiating early therapeutic options, large parts of the population do not get access to memory clinic-based assessments. Remote memory clinics facilitate low-level access to cognitive assessments by eschewing the need for face-to-face meetings. At the same time, patients with detected impairment or increased risk can receive non-pharmacological treatment remotely. Sensor technology can evaluate the efficiency of this remote treatment and identify cognitive decline. With remote and (partly) automatized technology the process of cognitive decline can be monitored but more importantly also modified by guiding early interventions and a dementia preventative lifestyle. We highlight how sensor technology aids the expansion of assessments beyond cognition and to other domains, e.g., depression. We also illustrate applications for aiding remote treatment and describe how remote tools can facilitate health education which is the cornerstone for long-lasting lifestyle changes. Tools such as transcranial electric stimulation or sleep-based interventions have currently mostly been used in a face-to-face context but have the potential of remote deployment-a step already taken with memory training apps. Many of the presented methods are readily scalable and of low costs and there is a range of target populations, from the worried well to late-stage dementia.

Phyllotaxis without symmetry: what can we learn from flower heads?

Phyllotaxis is commonly considered in the context of circular meristems or receptacles, yet non-circular (fasciated) structures also give rise to new primordia and organs. Here we investigate phyllotactic patterns in fasciated flower heads in the Asteraceae plant family. We begin by surveying the phenomenon of fasciation. We then show that phyllotactic patterns in fasciated heads can be generated by removing the inessential assumption of circularity from the previously published model of gerbera heads. To characterize these patterns, we revisit the conceptual framework in which phyllotactic patterns are commonly described. We note that some notions, in particular parastichies and parastichy numbers, maintain their significance in non-circular phyllotaxis, whereas others, in particular the divergence angle, need to be extended or lose their role. These observations highlight a number of open problems related to phyllotaxis in general, which may be elucidated by studies of fasciated heads.

Computational Models of Auxin-Driven Patterning in Shoots.

Auxin regulates many aspects of plant development and behavior, including the initiation of new outgrowth, patterning of vascular systems, control of branching, and responses to the environment. Computational models have complemented experimental studies of these processes. We review these models from two perspectives. First, we consider cellular and tissue-level models of interaction between auxin and its transporters in shoots. These models form a coherent body of results exploring different hypotheses pertinent to the patterning of new outgrowth and vascular strands. Second, we consider models operating at the level of plant organs and entire plants. We highlight techniques used to reduce the complexity of these models, which provide a path to capturing the essence of studied phenomena while running simulations efficiently.

Dysautonomia in the Ehlers-Danlos syndromes and hypermobility spectrum disorders-With a focus on the postural tachycardia syndrome.

Dysautonomia (autonomic dysfunction) occurs in the Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD). Symptoms include palpitations, dizziness, presyncope, and syncope, especially when standing upright. Symptoms of orthostatic intolerance are usually relieved by sitting or lying and may be exacerbated by stimuli in daily life that cause vasodilatation, such as food ingestion, exertion, and heat. Neurocardiovascular dysautonomia may result in postural tachycardia syndrome (PoTS), a major cause of orthostatic intolerance. It is defined by a rise in heart rate of >30 beats per minute (bpm) in adults and >40 bpm in teenagers while upright, without a fall in blood pressure (BP; orthostatic hypotension). In some, it can be compounded by the presence of low BP. For many, there is delay in clinicians recognizing the nature of the symptoms, and recognizing EDS or HSD, leading to delays in treatment. The onset of PoTS may be linked to an event such as infection, trauma, surgery, or stress. Gastrointestinal and urinary bladder involvement may occur, along with thermoregulatory dysfunction. In some, the mast cell activation syndrome may be contributary, especially if it causes vasodilatation. This paper reviews neurocardiovascular dysautonomia with an emphasis on PoTS, its characteristics, associations, pathophysiology, investigation, and treatment.

Remote monitoring technologies in Alzheimer's disease: design of the RADAR-AD study.

BACKGROUND: Functional decline in Alzheimer's disease (AD) is typically measured using single-time point subjective rating scales, which rely on direct observation or (caregiver) recall. Remote monitoring technologies (RMTs), such as smartphone applications, wearables, and home-based sensors, can change these periodic subjective assessments to more frequent, or even continuous, objective monitoring. The aim of the RADAR-AD study is to assess the accuracy and validity of RMTs in measuring functional decline in a real-world environment across preclinical-to-moderate stages of AD compared to standard clinical rating scales. METHODS: This study includes three tiers. For the main study, we will include participants (n = 220) with preclinical AD, prodromal AD, mild-to-moderate AD, and healthy controls, classified by MMSE and CDR score, from clinical sites equally distributed over 13 European countries. Participants will undergo extensive neuropsychological testing and physical examination. The RMT assessments, performed over an 8-week period, include walk tests, financial management tasks, an augmented reality game, two activity trackers, and two smartphone applications installed on the participants' phone. In the first sub-study, fixed sensors will be installed in the homes of a representative sub-sample of 40 participants. In the second sub-study, 10 participants will stay in a smart home for 1 week. The primary outcome of this study is the difference in functional domain profiles assessed using RMTs between the four study groups. The four participant groups will be compared for each RMT outcome measure separately. Each RMT outcome will be compared to a standard clinical test which measures the same functional or cognitive domain. Finally, multivariate prediction models will be developed. Data collection and privacy are important aspects of the project, which will be managed using the RADAR-base data platform running on specifically designed biomedical research computing infrastructure. RESULTS: First results are expected to be disseminated in 2022. CONCLUSION: Our study is well placed to evaluate the clinical utility of RMT assessments. Leveraging modern-day technology may deliver new and improved methods for accurately monitoring functional decline in all stages of AD. It is greatly anticipated that these methods could lead to objective and real-life functional endpoints with increased sensitivity to pharmacological agent signal detection.

Phyllotactic patterning of gerbera flower heads.

Phyllotaxis, the distribution of organs such as leaves and flowers on their support, is a key attribute of plant architecture. The geometric regularity of phyllotaxis has attracted multidisciplinary interest for centuries, resulting in an understanding of the patterns in the model plants Arabidopsis and tomato down to the molecular level. Nevertheless, the iconic example of phyllotaxis, the arrangement of individual florets into spirals in the heads of the daisy family of plants (Asteraceae), has not been fully explained. We integrate experimental data and computational models to explain phyllotaxis in Gerbera hybrida We show that phyllotactic patterning in gerbera is governed by changes in the size of the morphogenetically active zone coordinated with the growth of the head. The dynamics of these changes divides the patterning process into three phases: the development of an approximately circular pattern with a Fibonacci number of primordia near the head rim, its gradual transition to a zigzag pattern, and the development of a spiral pattern that fills the head on the template of this zigzag pattern. Fibonacci spiral numbers arise due to the intercalary insertion and lateral displacement of incipient primordia in the first phase. Our results demonstrate the essential role of the growth and active zone dynamics in the patterning of flower heads.

Effects of Oxytocin on Emotion Recognition in Schizophrenia: A Randomized Double-Blind Pilot Study.

BACKGROUND: Schizophrenia (SCZ) is a neurodevelopmental disorder that leads to poor social function. Oxytocin (OXT), a neuropeptide involved in social cognition, is a potential therapeutic agent for alleviating social dysfunction. Therefore, we investigated the effects of intranasal oxytocin (IN-OXT) on emotional processes in experimental interactive social contexts in individuals with SCZ. METHODS: In a male-only parallel randomized placebo-controlled double-blind trial, we investigated the effects of IN-OXT (24 IU) on visual fixation on pictures of faces and emotion recognition in an interactive ball-tossing game that probed processing of social and nonsocial stimuli. RESULTS: Intranasal oxytocin enhanced the recognition of emotions during an emotion-based ball-tossing game. This improvement was specific to the game that included social cue processing. Intranasal oxytocin did not affect eye gaze duration or gaze dwell time on faces in these patients. CONCLUSIONS: An acute low dose of IN-OXT had a modest effect on social cue processing and was limited to emotion recognition. Higher doses and long-term trials targeting emotional processing in SCZ may lead to improved social function.

Autonomic Dysfunction in Autism Spectrum Disorder.

Background: There have been previous reports of enhanced sympathoexcitation in autism spectrum disorder (ASD). However, there has been no formal investigation of autonomic dysfunction in ASD. Also, the joint hypermobile form of Ehlers-Danlos syndrome (hE-DS) that maybe overrepresented in ASD and orthostatic related autonomic dysfunction. This study examined the comorbidity of ASD, autonomic dysfunction and hE-DS in two UK autonomic national referral centers. Proven, documented and globally accepted clinical autonomic investigations were used to assess neuro-cardiovascular autonomic function in a cohort of ASD subjects and in age-matched healthy controls. Methods: Clinical data from 28 referrals with a confirmed diagnosis of ASD over a 10-year period were compared with 19 age-matched healthy controls. Autonomic function was determined using methods established in the centers previously described in detail. Results: 20/28 ASD had a diagnosed autonomic condition; 9 had the postural tachycardia syndrome (PoTS), 4 PoTS and vasovagal syncope (VVS), 3 experienced presyncope, 1 essential hyperhidrosis, 1 orthostatic hypotension, 1 VVS alone and 1 a combination of PoTS, VVS and essential hyperhidrosis. 16/20 ASD with autonomic dysfunction had hE-DS. In ASD, basal heart rate and responses to orthostatic tests of autonomic function were elevated, supporting previous findings of increased sympathoexcitation. However, sympathetic vasoconstriction was impaired in ASD. Conclusion: Intermittent neuro-cardiovascular autonomic dysfunction affecting heart rate and blood pressure was over-represented in ASD. There is a strong association with hE-DS. Autonomic dysfunction may further impair quality of life in ASD, particularly in those unable to adequately express their experience of autonomic symptoms.

The effect of mixing and free-floating carrier media on bioaerosol release from wastewater: a multiscale investigation with Bacillus globigii.

Aeration tanks in wastewater treatment plants (WWTPs) are significant sources of bioaerosols, which contain microbial contaminants and can travel miles from the site of origin, risking the health of operators and the general public. One potential mitigation strategy is to apply free-floating carrier media (FFCM) to suppress bioaerosol emission. This article presents a multiscale study on the effects of mixing and FFCM on bioaerosol release using Bacillus globigii spores in well-defined liquid media. Bioaerosol release, defined as percentage of spores aerosolized during a 30 minute sampling period, ranged from 6.09 × 10-7% to 0.057%, depending upon the mixing mode and intensity. Bioaerosol release increased with the intensity of aeration (rotating speed in mechanical agitation and aeration rate in diffused aeration). A surface layer of polystyrene beads reduced bioaerosol released by >92% in the bench-scale studies and >74% in the pilot-scale study. This study discovered strong correlations (R2 > 0.82) between bioaerosol release and superficial gas velocity, Froude number, and volumetric gas flow per unit liquid volume per minute. The Reynolds number was found to be poorly correlated with bioaerosol release (R2 < 0.5). This study is a significant step toward the development of predictive models for full scale systems.

The Role of Heart Rate Variability in the Future of Remote Digital Biomarkers.

Heart rate variability (HRV) offers insights into humoral, neural and neurovisceral processes in health and disorders of brain, body and behavior but has yet to be fully potentiated in the digital age. Remote measurement technologies (RMTs), such as, smartphones, wearable sensors or home-based devices, can passively capture HRV as a nested parameter of neurovisceral integration and health during everyday life, providing insights across different contexts, such as activities of daily living, therapeutic interventions and behavioral tasks, to compliment ongoing clinical care. Many RMTs measure HRV, even consumer wearables and smartphones, which can be deployed as wearable sensors or digital cameras using photoplethysmography. RMTs that measure HRV provide the opportunity to identify digital biomarkers indicative of changes in health or disease status in disorders where neurovisceral processes are compromised. RMT-based HRV therefore has potential as an adjunct digital biomarker in neurovisceral digital phenotyping that can add continuously updated, objective and relevant data to existing clinical methodologies, aiding the evolution of current "diagnose and treat" care models to a more proactive and holistic approach that pairs established markers with advances in remote digital technology.

Selecting Remote Measurement Technologies to Optimize Assessment of Function in Early Alzheimer's Disease: A Case Study.

Despite the importance of function in early Alzheimer's disease (AD), current measures are outdated and insensitive. Moreover, COVID-19 has heighted the need for remote assessment in older people, who are at higher risk of being infection and are particularly advised to use social distancing measures, yet the importance of diagnosis and treatment of dementia remains unchanged. The emergence of remote measurement technologies (RMTs) allows for more precise and objective measures of function. However, RMT selection is a critical challenge. Therefore, this case study outlines the processes through which we identified relevant functional domains, engaged with stakeholder groups to understand participants' perspectives and worked with technical experts to select relevant RMTs to examine function. After an extensive literature review to select functional domains relevant to AD biomarkers, quality of life, rate of disease progression and loss of independence, functional domains were ranked and grouped by the empirical evidence for each. For all functional domains, we amalgamated feedback from a patient advisory board. The results were prioritized into: highly relevant, relevant, neutral, and less relevant. This prioritized list of functional domains was then passed onto a group of experts in the use of RMTs in clinical and epidemiological studies to complete the selection process, which consisted of: (i) identifying relevant functional domains and RMTs; (ii) synthesizing proposals into final RMT selection, and (iii) verifying the quality of these decisions. Highly relevant functional domains were, "difficulties at work," "spatial navigation and memory," and "planning skills and memory required for task completion." All functional domains were successfully allocated commercially available RMTs that make remote measurement of function feasible. This case study provides a set of prioritized functional domains sensitive to the early stages of AD and a set of RMTs capable of targeting them. RMTs have huge potential to transform the way we assess function in AD-monitoring for change and stability continuously within the home environment, rather than during infrequent clinic visits. Our decomposition of RMT and functional domain selection into identify, synthesize, and verify activities, provides a pragmatic structure with potential to be adapted for use in future RMT selection processes.

Implementing Remote Memory Clinics to Enhance Clinical Care During and After COVID-19.

Social isolation is likely to be recommended for older adults due to COVID-19, with ongoing reduced clinical contact suggested for this population. This has increased the need for remote memory clinics, we therefore review the literature, current practices and guidelines on organizing such remote memory clinics, focusing on assessment of cognition, function and other relevant measurements, proposing a novel pathway based on three levels of complexity: simple telephone or video-based interviews and testing using available tests (Level 1), digitized and validated methods based on standard pen-and-paper tests and scales (Level 2), and finally fully digitized cognitive batteries and remote measurement technologies (RMTs, Level 3). Pros and cons of these strategies are discussed. Remotely collected data negates the need for frail patients or carers to commute to clinic and offers valuable insights into progression over time, as well as treatment responses to therapeutic interventions, providing a more realistic and contextualized environment for data-collection. Notwithstanding several challenges related to internet access, computer skills, limited evidence base and regulatory and data protection issues, digital biomarkers collected remotely have significant potential for diagnosis and symptom management in older adults and we propose a framework and pathway for how technologies can be implemented to support remote memory clinics. These platforms are also well-placed for administration of digital cognitive training and other interventions. The individual, societal and public/private costs of COVID-19 are high and will continue to rise for some time but the challenges the pandemic has placed on memory services also provides an opportunity to embrace novel approaches. Remote memory clinics' financial, logistical, clinical and practical benefits have been highlighted by COVID-19, supporting their use to not only be maintained when social distancing legislation is lifted but to be devoted extra resources and attention to fully potentiate this valuable arm of clinical assessment and care.

MOrPH-PhD: An Integrated Phage Display Platform for the Discovery of Functional Genetically Encoded Peptide Macrocycles.

Macrocyclic peptides represent attractive scaffolds for targeting protein-protein interactions, making methods for the diversification and functional selection of these molecules highly valuable for molecular discovery purposes. Here, we report the development of a novel strategy for the generation and high-throughput screening of combinatorial libraries of macrocyclic peptides constrained by a nonreducible thioether bridge. In this system, spontaneous, posttranslational peptide cyclization by means of a cysteine-reactive noncanonical amino acid was integrated with M13 bacteriophage display, enabling the creation of genetically encoded macrocyclic peptide libraries displayed on phage particles. This platform, named MOrPH-PhD, was successfully applied to produce and screen 105- to 108-member libraries of peptide macrocycles against three different protein targets, resulting in the discovery of a high-affinity binder for streptavidin (K D: 20 nM) and potent inhibitors of the therapeutically relevant proteins Kelch-like ECH-associated protein 1 (K D: 40 nM) and Sonic Hedgehog (K D: 550 nM). This work introduces and validates an efficient and general platform for the discovery and evolution of functional, conformationally constrained macrocyclic peptides useful for targeting proteins and protein-mediated interactions.